TRNA-derived fragments (tRFs) as regulators of oncogenes and tumor suppressor genes in head and neck squamous cell carcinoma.

Abstract

e18082 Background: Roughly 50,000 individuals are diagnosed with head and neck cancers in the United States yearly. Though risk factors and common therapeutic strategies are well-established, early detection of head and neck cancers remains challenging. One strategy for early detection is high-throughput analysis of both coding and noncoding RNA transcripts, which has become increasing implicated in cancer pathogenesis. One such noncoding transcript is tRNA-derived fragments (tRFs), which are the products of enzymatic cleavage of precursor tRNAs. Though tRFs have been suggested to play important roles in the regulation of mRNA translation (similar to other noncoding RNAs), their utility as cancer biomarkers is not well-known. Methods: In this study, we investigate tRFs for correlation to cancer prevalence with specific consideration of translational regulation of oncogenes (OG) and tumor suppressor genes (TSG). tRF read counts were obtained for 499 head and neck squamous cell carcinoma tumor tissue samples and 44 adjacent normal samples. Results: The read counts between both groups were compared to identify tRFs dysregulated in tumor samples, which may be pertinent biomarkers for diagnosis. Ten tRFs were found to be significantly dysregulated in cancer samples. These tRFs were further assessed for correlation to expression of OGs and TSGs using the COSMIC database. Due to the mRNA-degrading nature of tRFs, we analyzed tRF abundance for inverse correlation to gene expression. Four tRFs upregulated in tumor samples showed significant anticorrelation to select TSG expression (ATP2B3, CSMD3, LZTR1, NTHL1, PTPRC), and three tRFs downregulated in tumor samples showed anticorrelation to OG expression (A1CF, MPL, SALL4, TNC). Notably, LeuCAG 5’ tRF was associate with high binding affinity for the TSGs CSMD3 and LZTR1, supporting the likelihood of tRF-mediated degradation. Interestingly, this tRF was inversely correlated with patient survival length. LeuCAG 5’ was also of significantly lesser abundance in patients who experienced complete or partial remission following chemotherapy treatment, further indicating this tRFs’ clinical relevance in HNSCC, potentially as an oncogenic-related agent. Conclusions: Investigation into these tRFs may reveal their potential for use in early diagnosis. High abundance of this tRF may be indicative of oncogenesis. In exploring tRFs’ for their potential as biomarkers of cancer, they may prove useful in allowing earlier diagnosis. Moreover, studying tRFs may provide additional considerations for patient care and treatment.